This application is directed to an improved skin cream composition for the treatment and minimization of the appearance of wrinkles and a method for the transdermal delivery thereof.
Physical appearance, beauty, and the desire to maintain youthfulness are concepts that are not new. In all societies around the world, there are easily recognizable incentives regarding the maintenance of a favorable appearance. The nature and form of desirable appearance varies, but each culture has developed its own standards and norms. In our modern society, psychologists, sociologists, and economists, as well as those on Madison Avenue, have made observations about our attitudes regarding appearance. Cosmetologists, health experts, personal trainers, and cosmetic surgeons have supplied us with various means by which we can maintain our youthful appearance and improve the undesired and undesirable changes of aging. Aging and aging of the face are the results of many factors. Some of these are intrinsic, some extrinsic. Some are controllable, some uncontrollable. The rate at which different people age is variable. Aging on a biologic basis is not a homogenous, even-flowing process, but appears to evolve with various accelerations and decelerations. Individuals appear to age at different rates; however, we all age in a similar progression, and therefore discernable patterns emerge.
The aging process is believed to be based on the same principles in every individual. The intrinsic aspects of aging are largely based on heredity; these are programmed into the individual at the cellular level and are largely unalterable. The extrinsic factors are the results of an individual's habits, nutrition, and exposure to deleterious factors, such as cigarette smoking and ultraviolet sunlight. The individual can influence or control the extrinsic factors largely by avoidance and through the maintenance of good health habits and exercise. Once the observable changes of aging have occurred, few are reversible. Many of the changes, however, can be improved through makeup, cosmetic skin care, and cosmetic rejuvenative surgery.
Histologically, sun-damaged epidermis is significantly thickened and disorganized as compared to non-damaged skin. In response to long-term exposure to sun, epidermal melanocytes enlarge, proliferate and migrate to higher levels of the epidermis. Chronic stimulation of melanocyte often leads to dyschromia, spotty hyper pigmentation, and the proliferation of pigmented keratosis. It is also known that ultraviolet radiation causes extensive damage to both cellular and structural components of the dermis.
Nutritionists have long warned about the deleterious effects of free radicals. Indeed it has been well documented that significant damage to biological tissues results from free radical induced oxidation. The presence of oxidation inducing free radicals is promoted by exposure to several environmental factors. Among these factors are air pollutants, ultraviolet radiation, diet and cosmetic agents. Dermatologically, the presence of free radicals promotes and sometimes accelerates the aging process. One result of this acceleration would be the observance of wrinkles. Indeed, similar concerns regarding free radical induced damage to the skin has as well been documented.
The genetically determined process of the aging skin results in a predictive group of morphologic and physiologic changes. In the skin of an aged person, the epidermis is of variable thickness, there is modest diversity in cell size and shape, the dermatoepithelial abutment is flattened and rete ridges are lost, cumulatively rendering aged skin fragile and susceptible to injury from sheering forces. The dermis of senescent skin is characterized by marked cellular atrophy and a corresponding reduction in metabolic activity. As a result, the percentage of newly synthesized collagen in the dermis decreases. As a result, aged or aging skin is less distensible, poorly resilient, and prone to fine wrinkling. Furthermore, in aging skin the epidermis thins with a gradual loss of rete ridges and concomitant decrease in cell turnover in the basal cells. Furthermore, the surface corneocyte layer thickens with age. The dermis also becomes thinner with decreased collagen content, degeneration of elastic fibrils, decreased water content, and the gradual addition of stable cross-links in and between collagen fibrils. Skin thickness in women reaches maximum at approximately age 35 and decreases gradually thereafter. In men, the skin thickness versus age curve is different, with the peak in skin thickness occurring at age 45. With these changes, there is a loss of the biomechanical properties of the skin and with advancing age, the ability of the skin to recover from the initial stages of deformation drops. The appearance of aged, sun-damaged skin is therefore the result of these intrinsically and extrinsically caused changes. The skin may have uneven pigmentation and an uneven texture, may be wrinkled, less distensible, and more prone to laxity.
Fine wrinkles generally begin to appear in individuals in their twenties; these wrinkles deepen as individuals approach their thirties. In the upper face, crow's feet and wrinkling above the eyelids may occur as early as the late twenties. The formation of crow's feet is secondary to the contraction of the orbital portion of the orbicularis oculi muscle and they are accentuated by the elevation of the upper cheek by the zygomaticus and the zygomatic head of the quadratus labii superioris muscle.
Chronic exposure to ultraviolet light damages structural and functional components of the skin. The resulting photo-damage, or photo-aging as it is sometimes called, is characterized by wrinkling, sallowness, modeled hyper pigmentation, and laxity. Histologically, photo-damage is accompanied by epidermal thinning, variable atypia, large, irregular grouped melanocyte and elastosis. In 1986, Kligman et al. reported that tretinoan cream (Retinin-A), which had been used for more than twenty years in the treatment of acne vulgaris, could also produce a more attractive, less-wrinkled skin in older patients. When applied to persons with photo-damaged skin, tretinoan cream proved effective in partially reversing structural skin damage. In the past ten years, clinical and histologic studies have confirmed the efficacy of tretinoan as therapy for smoothing skin texture, reducing wrinkles, and improving skin discoloration. Further research by Kligman et al. studied the efficacy of topical tretinoan cream on reversing facial skin photo-damage. Elderly patients received a daily facial application of 0.05% tretinoan cream for six to twelve months and six age-matched subjects received a placebo vehicle only. Although clinical changes were deemed to be slight, many histologic effects were observed in skin biopsy specimens. One of the clinical changes observed from this research included normalization of various skin structures such as thickening of a previously atrophic epidermis, elimination of dysplasia and atypia, and more uniform dispersion of melanin and the formation of new dermal collagen and blood vessels. Furthermore, topical tretinoan has been shown to have beneficial effects in the treatment of hyper pigmented lesions of a variety of types such as those associated with photo-damage in white patients, and those caused by inflammation or melasma in black patients. Additionally, "liver spots" on the face or upper extremities of patients with photo-damage were treated with 0.1% tretinoan cream daily, resulting in a lightening of the liver spots (more appropriately called hyper pigmented macules or also termed actinic lentigines). However, tretinoan frequently induces mild to moderate dermatitis. Although, percutaneously absorbed tretinoan has no detectible effect on plasma concentrations of the drug and its metabolites in any of the protocols reported, many patients see the induced mild to moderate dermatitis as prohibitively discomforting for effective use in correction of wrinkles.
Much work has been directed towards the use of topically applied organic acids, which cause a destruction and subsequent removal of the outer dermis layers, thereby provoking the formation of new collagen. It is believed that the induced formation of new collagen would occur preferentially over old collagen, thereby replacing wrinkles with new, young dermis in the absence of said wrinkles. Previous works with chemical peels, as they are known, discuss the post-peel development of a zone of collagen. The zone of collagen is a deposit of a new collagen that is laid down in the upper dermal layers after a chemical peel. Both phenol and trichloracetic acids (TCAs) have been histologically studied to compare the amount of new deposition in the zone of collagen. The deeper depth of necrosis caused by the chemical peeling agent resulted in a deeper zone of collagen. Thus, more damaging chemical peels can smooth deeper layers of the skin. For instance, higher concentrations of trichloracetic acid, perhaps 50-70%, can penetrate to layers of the reticular dermis and also cause a zone of new collagen to that same depth. However, higher concentrations of trichloracetic acid can lead to scarring, and other severe risks involved with trichloracetic acid use. Although it is true that trichloracetic acids may be applied at a lesser concentration, the same types of risks are involved as are present with a higher concentration because of the inherent strength of the acid involved.
.alpha.-Hydroxy acids (AHAs) have been used for many years as exfoliants, moisturizers, and emollients. Lactic acid salts, most notably sodium lactate, have been hypothesized to be part of the skin's own natural moisturizing system. In addition, AHAs and salicylic acid, a structurally similar .beta.-hydroxy acid, have been used for at least 40 years as peeling agents.
Studies have shown that several AHAs (as well as .beta.-hydroxy and carboxylic acids) in low concentration (5%) stimulate epidermal turnover or cell renewal (exfoliation) and have the potential to irritate the skin. This activity is closely linked to acidic pH as neutralized acids lose their ability to exfoliate the skin.
The moisturizing activity of AHAs and their ability to exfoliate the skin and interfere with intercellular cohesion in the outer epidermis are well documented. It is suggested that AHAs interfere with cohesion in the stratum granulosum, unlike salicylic acid and other exfoliants.
Several studies on the activity of a buffered 12% ammonium lactate lotion have documented its moisturizing activity (Wehr et al. Controlled two-center study of lactate 12 percent lotion and a petrolatum-based cream in patients with xerosis, Cutis, 37:205-9 (1986); Grove, The effect of moisturizers on skin surface hydration as measured in vivo by electrical conductivity, Curr. Ther. Res. Clin. Exp., 50:712-9 (1991); and Breener, The efficacy of 12 percent ammonium lactate in the treatment of dry skin of the feet. A clinical product review, J. Curr. Podiatr. Med., 37:15-7(1988)). Lavker et al., Effects of topical ammonium lactate on cutaneous atrophyfrom a potent tropical corticosteroid, J. Am. Acad. Dermatol., 26:535-44 (1992), found that ammonium lactate caused an increase in dermal ground substance and increased glycosaminoglycan synthesis. Murad et. al., The use of glycolic acid as a peeling agent, Dermatological Clinic on Cosmetic Dermatology, Murad H, editor, Philadelphia: WB Saunders, (1995), demonstrated that aggressive glycolic acid peels significantly increase collagen and dermal ground substance. Precisely how and why AHAs produce these effects is not known.
Vitamin C (ascorbic acid) is alleged to protect the brain and spinal cord from free radicals. It promotes collagen (connective tissue) synthesis, lipid (fat) and carbohydrate metabolism, and the synthesis of neurotransmitters. It is also essential for optimum maintenance of the immune system. Vitamin C is toxic to a wide range of cancer cells, especially melanoma. The oxidizing enzyme tyrosine that catalyzes the aerobic action of tyrosine into melanin and other pigments is also inhibited by the presence of Vitamin C. Vitamin C has been found to be effective in catalyzing the immune response to many viral and bacterial infections. Besides the many applicable uses set forth above, Vitamin C is essential for collagen synthesis and wound healing. International patent application, WO 96/14822, published May 23, 1996, and corresponding U.S. Pat. No. 5,785,978, issued Jul. 28, 1998, teach that concentrated dry powdered antioxidants, Vitamin C and its salts in particular, may be compounded with adhesives and applied to target areas where wrinkles develop to ameliorate photo, oxidative and stress damage and improve skin appearance. However, it is to be noted that only the use of ascorbic acid is shown and the adhesive/ascorbic acid compositions illustrated resulted in adhesive remaining on the skin of the wearer when a patch containing the adhesive composition was removed. Also, application of such patches to sensitive areas, such as around the eyes, often results in pain and trauma during the removal process.
Modern environmental conditions, such as heating and air conditioning, exposure to the sun, and environmental pollution exert severe stress on the skin and accelerate the natural aging process resulting in wrinkles, decreased firmness and elasticity, dryness and other cosmetically undesirable effects. Although a number of skin cream compositions already exist, there is a need for a simple-to-apply and effective all-in-one cosmetic treatment, such as a skin preparation that can counteract and minimize, simultaneously, distresses on the skin and improve firmness and elasticity while it counteracts dryness so that wrinkles and other undesirable effects appearing on the skin are corrected or at least delayed.
Many formulations have been developed which focus on a few accepted skin treatment regimes. Moreover, many of the available skin treatment systems do not adequately prevent and treat the multitude of hazards which deleteriously impact the skin.